The Human Immunodeficiency Virus (HIV) is the etiological agent of AIDS. To date there are only three FDA approved drugs which provide direct antiviral activity against this virus, and both toxicities and emerging resistance limit their widespread utility. In order for new and efficacious anti-HIV agents to enter human clinical trials, small animal models are required to demonstrate in vivo activity. Since HIV is a uniquely human virus, novel means are required to introduce this virus into rodent hosts. One such means is through the xenotransplantation of human HIV permissive cells into sublethally irradiated athymic mice. It is the overall objective of this proposal to fully validate the "Irradiated, Nude Mouse, HIV/Human Cell Xenotransplant System" for the preclinical efficacy evaluation of potential therapeutic drugs for the treatment of Human Immunodeficiency Virus (HIV) infection. In order to meet this objective, the following specific aims for the Phase II proposal will be pursued: 1) Expanding the quantitative viral replication parameters used and the number of data points gathered to further elucidate viral replication kinetics in the model (i.e., p24 antigenemia, indirect immunofluorescent assays, recovery and titration of infectious virus from plasma and infected cells, and quantitative viral RNA and DNA assays; 2) Extensive testing of AZT as the standard efficacy (e.g. dose ranging, delayed or short term therapeutic administration); 3) Testing of other established antiretrovirals and promising compounds previously shown effective against HIV in vitro or in other model systems; and 4) Multiple agent testing for additive and/or synergistic effects. The results will show that the xenotransplantation of HIV-infected cells into nude mice can provide a cost-effective, predictive mode in which to test putative anti- HIV compounds. PROPOSED COMMERCIAL APPLICATION: Many pharmaceutical companies currently have drugs which are being investigated for anti-HIV activity. With public pressure for the FDA to approve these drugs more rapidly, these companies are faced with placing these drugs into clinical trials early, and/or using simian trials. Our proprietary animal model has the potential to accelerate drug development, and reduce costs for these clients.